The invention relates to a method of inhibiting cellular and humoral responses to immunostimulatory DNA with compositions including 4-aminoquinolines, 9-aminoacridines and derivatives thereof.
Bacterial DNA is increasingly recognized as a powerful modulator of immunity (Krieg, 1997. Trends in Microbiol. 4:73-6), stimulating the polyclonal proliferation of B-cells and the production of cytokines by monocytes and other cells (Ballas et al., 1996. J. Immunol. 157:1840-5). This activity is attributed to unmethylated CpG sequences in bacterial DNA, which are uncommon in vertebrate DNA (Krieg et al., 1995. Nature 374:546-9). Single stranded oligodeoxynucleotides which have the motif PuPuCGPyPy (CpG-ODN) mimic many of the actions of bacterial DNA (Krieg et al., 1996. Antisense & Nucleic Acid Drug Devel. 6:133-9), and powerfully inhibit the induction of apoptosis in mouse WEHI 231 B-cells by anti-surface 1 gM (Yi et al., 1996. J. Immunol. 157:4918-25; Macfarlane et al., 1997. Immnunology 91:586). This system is a convenient and reproducible model to study responses to immunostimulatory DNA.
Bacterial DNA immobilized on beads does not stimulate immune responses, suggesting that internalization of the DNA is required for activity. DNA and oligodeoxynucleotides are endocytosed into acidic vesicles, and are then transported to the cytoplasm and nucleus of cells.
Chloroquine, hydroxychloroquine and quinacrine are known to induce remissions of systemic lupus erythematosus and rheumatoid arthritis by an unknown mechanism. These drugs bind to DNA by intercalation. They are weak bases and partition into acidic vesicles. At high concentrations, chloroquine can collapse the pH gradient and disrupt the action of endosomal hydrolytic enzymes and the trafficking of receptors.